This proposal centers around the interrelationships between the effects of ethanol ingestion on lipid metabolism and how these effects are altered by changing some of the constituents of the diet. After the ingestion of ethanol, one of the earliest biochemical changes which occur in liver and heart is a shifting in the balance between the oxidation and esterification of fatty acids towards esterification. Therefore, I propose to study the mechanism by which ethanol metabolism alters this balance in both liver and heart. To do this, the diets will be altered by changing the carbohydrate and lipid components and determining how this alters the effects of ethanol on carnitine acyltransferase and phosphatidate phosphohydrolase. These enzymes are associated with several subcellular or submitochondrial fractions. Thus, they will be fractionated and at least partially purified to determine if ethanol has a selective effect on one particular form. The studies on the acyl-CoA: carnitine acyltransferases will be continued in an effort to understand more clearly how this enzyme is regulated and what role it plays in fatty acid oxidation. Other measurements will include polarographic studies on the oxidation of fatty acids and other mitochondiral substrates. Further, studies will be done to determine the mechanism by which ethanol increases the oxidation of choline and to determine if choline is related to the production of alcoholic fatty liver. Both acute and chronically treated animals will be utilized, and dietary manipulations (see above) will be used in an effort to correlate the in vitro experiments outlined above with the in vivo. The overall goal of this work is an understanding of the factors controlling lipid metabolism and how ethanol alters them. If this can be accomplished, then significant strides can be made in approaching treatment and in understanding the biochemical alterations leading to cirrhosis and alcoholic liver disease. BIBLIOGRAPHIC REFERENCES: Thompson, J.A. and R.C. Reitz. "Studies on the Mechanism of the NADPH-catalyzed Peroxidation of Endogenous Lipid." Biochim. Biophys. Acta. 398:159-171 (1975). Thompson, J.A. and R.C. Reitz. "Studies on the Acute and Chronic Effect of Ethanol Ingestion on Choline Oxidation." Ann. N.Y. Acad. Sci. 273:194-204 (1976).